Among cardiovascular drugs, Angiotensin II receptor antagonists like losartan potassium are prominently used as an active ingredient in the management of hypertension. Losartan potassium plays an effective role in patients having difficulty in tolerating ACE inhibitors. The chemical name of losartan potassium is 2-n-Butyl-4-Chloro-1[((2′-tetrazol-5-yl)-1,1′-bisphenyl-4-yl)methyl]-imidazole-5-methanol potassium.
It is known in the art to synthesize losartan potassium from the acid form of losartan. Losartan potassium (shown as the compound of formula (I) below) is known in the art as able to be synthesized by reacting its acid (shown as the compound of formula (II) below) with KOH. The intermediate acid form (II) in turn is known as able to be synthesized by detritylation of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[((2′-triphenylmethyltetrazole-5-yl)biphenyl-4-yl)methyl]imidazole (shown as the compound of formula (III) below).
The synthesis of Trityl Losartan (the reactant of form (I) below) is known in the art. See 34 J. MED. CHEM. 2525-27 (1991); 59 J. ORG. CHEM. 6391-94 (1994) U.S. Pat. No. 5,138,069). Trityl Losartan (and the Losartan acid) and may alternatively be prepared using the reactions and techniques described in U.S. Pat. No. 5,138,069 and patent application number WO93/10106. 
The preparation from Trityl Losartan (the reactant of form (III)) of Losartan acid (II) by acid-catalyzed cleavage of the trityl group from Trityl Losartan (III) is disclosed in U.S. Pat. No. 5,281,603. Another method disclosed to prepare Losartan acid from trityl losartan is disclosed in U.S. Pat. No. 5,281,604; in this process, Trityl Losartan (III) is refluxed in a mixture of methanol and tetrahydrofuran for 18 hours to get losartan acid (II).
Similarly, in patent application number WO01/81336, Richter Gedeon describes treatment of Trityl Losartan (III) with potassium hydroxide in primary alcohols and crystallization of the product (I) from methanol with the help of anti-solvents such as dipolar aprotic solvent (acetonitrile), aprotic solvent (straight or branched chain or cyclic aliphatic hydrocarbons) or a protic solvent (sec-butanol).
The Richter Gedeon approach was found to be easy and superior to the existing methods, however was found to suffer from various drawbacks as summarized below:                a) The product obtained does not pass desired solubility in various solvents. To make the product improve in quality, it needs an extra purification as per the Richter Gedeon application.        b) Purification step in the process, the resultant purity and the yields thereof, depend on very precise ratios of solvent mixture (e.g. methanol, cyclohexane or acetonitrile)        c) High volume of solvents in combination is used in purification which leads to capacity reduction of plant production/facilities.        d) Recovery and recyclability of the solvents (methanol and anti-solvents) from its mixture is difficult and needs careful purification by distillation to get recyclable solvents. Production of waste is more with no economic value and high pollution load in the non-recovery option.Patent application number WO 02/094816, discloses use of acetone, ethyl acetate, acetonitrile and toluene as anti-solvents and has similar problems of recovery and reuse of solvents and high cost of production. Since isolation of the product is simply by precipitation using anti-solvents, the product needs further purification to pass the required tests, in this case also.        
The art teaches not only the need for purifying the resulting losartan potassium (I), the art teaches various methods to purify it. For example, U.S. Pat. No. 5,608,075 discloses two polymorphic forms of Losartan Potassium, which are form I and form II. Their method of preparation and characterization by X-ray powder diffraction pattern, DSC thermograms, FT-IR spectra, Raman spectra and C13 NMR (solid state) spectra is also given. The disclosed procedure for polymorphic form I is the addition of aqueous solution of (I) to a refluxing mixture of cyclohexane and isopropyl alcohol followed by azeotropic distilling out cyclohexane/isopropyl alcohol/water ternary azeotrope at 64° C. while the form I crystallizes out at 69° C.
Patent application number WO 98/18787 describes a method which also starts with a solution of Losartan Potassium (I) in aqueous isopropyl alcohol and is heated to distill out water-isopropyl alcohol mixture to lower the water content to 2.6%. Further excessive seeding is carried out with slurry of Losartan Potassium (I) in cyclohexane until the seed remains undissolved. The precipitation of the product is then achieved by continuous distillation of ternary azeotrope with simultaneous addition of cyclohexane to the reaction mass. This azeotrope distillation is carried out until moisture level decreases to about 0.2 to 0.11%. The crystallized product thus obtained is filtered.